Coating and binding agent for pharmaceutical formulations with improved storage stability

ABSTRACT

The invention relates to a process for the preparation of a coating and binding agent for oral or dermal pharmaceutical forms, essentially consisting of (a) a copolymer consisting of free-radical-polymerized C1 to C4 esters of acrylic or methacrylic acid and further (meth)acrylate monomers which contain functional tertiary ammonium groups, the coplymer being present in powdered form having an average particle size of 1–40 μm, (b) 3 to 15% by weight, based on (a), of an emulsifier having an HLB of at least 14 and (c) 5 to 50% by weight, based on (a), of a C 12 —to C 18 -monocarboxylic acid or a C 12 —to C 18 -hydroxyl compound, the components (a), (b) and (c) being blended or mixed with one another with or without addition of water and if appropriate with addition of a pharmaceutical active compound and further customary additives and the coating and binding agent being produced from the mixture by melting, casting, spreading or spraying. The invention further relates to the coating and binding agent itself.

The invention relates to a coating and binding agent for pharmaceuticalformulations having improved storage stability.

PRIOR ART

WO 00/05307 describes a process for the production of a coating andbinding agent for oral or dermal pharmaceuticals consisting of (a)35–98% by weight of a copolymer consisting of free-radical-polymerizedC1- to C4-esters of acrylic or methacrylic acid and further(meth)acrylate monomers which have functional tertiary ammonium groupsand (b) 1–50% by weight of a plasticizer and 1–15% by weight of anemulsifier having an HLB of at least 14, the components (a), (b) and (c)being blended with one another with or without addition of water andoptionally with addition of a pharmaceutical active compound and furthercustomary additives and the coating and binding agent being produced bymelting, casting, spreading or spraying, the copolymer (a) beingincorporated in powder form having an average particle size of 1–40 μm.

The formulation in the defined powder form in combination withplasticizer and emulsifier makes it possible to convert thecorresponding copolymers into stable aqueous solutions or dispersionswithout the addition of acids. There is the advantage that an otherwiseoccuring bitter intrinsic taste of the coating agent can be avoided. Thecoating and binding agents are moreover hardly soluble in water, butdissolve rapidly in artificial gastric juice. They are thereforeparticularly suitable for taste-isolating formulations which rapidlydecompose in the gastric juice. No details are contained on the waterpermeability of the coatings.

OBJECT AND ACHIEVEMENT

While a whole series of pharmaceutical active compounds are very stablein dry air, they are sensitive to moisture and moisture-related pHshifts in the alkaline pH range. The storage conditions for coated orbound pharmaceutical formulations are not optimum everywhere, so that,for example, in tropical regions it can perfectly well occur that suchpharmaceutical formulations are exposed to relatively high atmospherichumidities over a relatively long period before use. It is thereforegenerally important that as little moisture as possible can penetratethrough the pharmaceutical coatings or binding agents to the enclosedactive compound. It was therefore seen as an object to make availablecoating and binding agents for oral or dermal pharmaceutical forms whichguarantee a good isolation against the penetration of atmospherichumidity.

The invention starts essentially from WO 00/05307. The coating andbinding agents described there are in particular to be further developedto the effect that their water vapour permeability is improved withoutthe other properties such as rapid disintegration in artificial gastricjuice and good processability being adversely affected.

The object is achieved by a process for the production of a coating andbinding agent for oral or dermal pharmaceutical forms consistingessentially of

-   (a) a copolymer consisting of free-radical-polymerized C1- to    C4-esters of acrylic or methacrylic acid and further (meth)acrylate    monomers which have functional tertiary amino groups, the copolymer    being present in the powder form having an average particle size of    1–40 μm-   (b) 3 to 15% by weight, based on (a), of an emulsifier having an HLB    of at least 14-   (c) 5 to 50% by weight, based on (a), of a C₁₂- to    C₁₈-monocarboxylic acid or a C₁₂- to C₁₈-hydroxyl compound    the components (a), (b) and (c) being blended or mixed with one    another with or without addition of water and optionally with    addition of a pharmaceutical active compound and further customary    additives and the coating and binding agent being produced from the    mixture by melting, casting, spreading, spraying or granulating.

While coating and binding agents according to WO 00/05307 have watervapour permeabilities measured according to DIN 53 122 in the range of400 (g/m²/d) or above, the coating and binding agents according to theinvention lie at water vapour permeabilities of at most 350 (g/m²/d),preferably at most 300 (g/m²/d), particularly preferably at most 200(g/m²/d). It was not foreseeable that it would be possible to achievethis effect by the combination of the components (a), (b) to [sic] (c)without the known advantageous properties of coating and binding agentsaccording to WO 00/05307 being adversely affected. In particular, theuse of the component (c) also makes possible extensive or completerelinquishment of customary plasticizers. This is a further advantage,as efforts are always made to keep the number of the components inpharmaceutical formulations low.

CARRYING OUT THE INVENTION

Component (a)

The copolymers (a) consist essentially or entirely offree-radical-polymerized C1 to C4 esters of acrylic or methacrylic acidand further (meth)acrylate monomers which contain functional tertiaryamino groups.

Suitable monomers having functional tertiary amino groups are listed inU.S. Pat. No. 4,705,69, column 3, line 64 to column 4, line 13.Particular mention may be made of dimethylaminoethyl acrylate,2-dimethylaminopropyl acrylate, dimethylaminopropyl methacrylate,dimethyl-aminobenzyl acrylate, dimethylaminobenzyl methacrylate,(3-dimethylamino-2,2-dimethly)propyl acrylate,dimethylamino-2,2-dimethly)propyl methacrylate,(3-dimethylamino-2,2-dimethly)propyl acrylate anddiethylamino-2,2-dimethly)propyl methacrylate. Dimethylaminoethylmethacrylate is particularly preferred.

The content of the monomers having tertiary amino groups in thecopolymer can advantageously be between 30 and 70% by weight, preferablybetween 40 and 60% by weight. The proportions of the C1 to C4 esters ofacrylic or methacrylic acid is 70–30% by weight. Mention may be made ofmethyl methacrylate, ethyl methacrylate, butyl methacrylate, methylacrylate, ethyl acrylate, butyl acrylate.

A (meth)acrylate copolymer having tertiary amino groups corresponding tocomponent (a) can be synthesized, for example, from 20–30% by weight ofmethyl methacrylate, 20–30% by weight of butyl methacrylate and 60–40%by weight of dimethylaminoethyl methacrylate. The proportion ofcomponent (a) in the formulation is preferably 50–90% by weight.

The copolymers (a) are obtained in a manner known per se by free-radicalsubstance, solution, bead or emulsion polymerization. They must bebrought into the particle size range according to the invention beforeprocessing by means of suitable grinding, drying or spraying processes.Suitable equipment for the production of the powders is familiar to theperson skilled in the art, e.g. air-jet mills, pinned disc mills, fanmills. If desired, appropriate screening steps can be included. Asuitable mill for large industrial amounts is, for example, acounter-jet mill (Multi No. 4200) which is operated at about 6 baroverpressure.

The average particle size of the powders can be determined as follows:

By means of air-jet screening for the simple division of the groundproduct into a few fractions. This method is somewhat more inaccurate inthis measuring range than the alternatives. At least 70, preferably 90,% of the particles based on the mass (mass distribution), however,should be in the size range according to the invention of 1–40 μm,preferably 10–30 μm.

A highly suitable measuring method is laser scattering for determinationof the particle size distribution. Commercial apparatuses allowmeasurement in air (Malvern S3.01 particle sizer) or preferably inliquid media (LOT, Galai CIS 1). The prerequisite for measurement inliquids is the the polymer does not dissolve therein or the particleschange in another manner during the measurement. A suitable medium is,for example, a highly diluted (about 0.02% strength) aqueous polysorbate80 solution. The average particle diameter must be in the range between1 to 40, preferably between 5 and 35, in particular between 10 and 20μm.

Component (b)

Emulsifiers or surfactants are surface-active substances havinglyobipolar character, i.e. non-polar, lipophilic and polar, hydrophiliccentres must be present in their molecule (P. H. List,Arzneiformen-lehre, Wissenschaftliche Verlagsgesellschaft mbH Stuttgart,1982, Chap. 6.2.). Depending on the molecular structure, adifferentiation is made between ionic and non-ionic emulsifiers.

The HLB is a measure of the hydrophilicity or lipophilicity of non-ionicsurfactants introduced in 1950 by Griffin. It can be determinedexperimentally by means of the phenol titration method according toMarszall; cf. “Parfümerie, Kosmetik” (Perfumery, Cosmetics), Volume 60,1979, pp. 444–448; further references in Römpp, Chemie-Lexikon, 8^(th)Edition 1983, p. 1750. Furthermore see, for example, U.S. Pat. No.4,795,643 (Seth)).

An HLB (Hydrophilic/Lipophilic Balance) can only be determined exactlyin the case of non-ionic emulsifiers. In the case of anionicemulsifiers, this value can be determined arithmetically, but isvirtually always above or far above 14.

Emulsifiers (b) having an HLB of below 14 are understood according tothe invention as meaning hydrophilic, non-ionic emulsifiers having anHLB range of at least 14, and likewise hydrophilic, anionic emulsifiersand their salts which have an arithmetic HLB of over 14. Emulsifiershaving HLBs of less than 14, such as, for example, glycerolmonostearate, can indeed additionally also be contained, but do notreplace the emulsifiers (b) having HLBs of at least 14. Suitableemulsifiers (b) are, for example, sodium laurylsulphate and sodiumcetylstearylsulphate, sucrose stearate and polysorbate 80. Theemulsifiers (b) are present in amounts of 1–15, preferably 5–10, % byweight, based on component (a). Also possible, of course, is the use ofemulsifier mixtures.

The addition of the emulsifiers (b) to the formulation can be carriedout in a known manner, directly, in aqueous solution or after thermalpretreatment of the mixture.

Depending on type (lipophilic or hydrophilic) and amount added, theemulsifiers can influence the functionality of the polymer layer.

Component (c)

Component (c): 5 to 50, preferably 10 to 20, % by weight (based on thecomponent (a)) of a C₁₂- to C₁₈-monocarboxylic acid or of a C₁₂- toC₁₈-hydroxyl compound. The component (c) is crucial for the surprisinglylow water vapour permeability of the formulations.

Unbranched C₁₂- to C₁₈-monocarboxylic acid or of a C₁₂- to C₁₈-hydroxylcompounds [sic] are preferred. Optionally, branched derivatives of thesubstances mentioned can also be suitable.

C₁₂- to C₁₈-monocarboxylic acids are, for example, in particular, lauricacid and myristic acid. Palmitic acid and stearic acid are preferred.

C₁₂- to C₁₈-hydroxyl compound, in particular alkanols having a terminalhydroxyl group such as, for example, lauryl alcohol or stearyl alcohol.

Further Additives

As a rule, during processing to give coating and binding agentscustomary additives are added to the formulation according to theinvention.

The amounts employed and use of the customary additives inpharmaceutical films or coatings are familiar to the person skilled inthe art. Customary additives can be, for example, release agents,pigments, stabilizers, antioxidants, pore formers, penetrationpromoters, lustre agents, aromatic substances or flavourings. They serveas processing aids and are intended to guarantee a safe and reproduciblepreparation process and good long-term storage stability or they achieveadditional advantageous properties in the pharmaceutical form. They areadded to the polymer preparations before processing and can influencethe permeability of the coatings, which can optionally be utilized as anadditional control parameter.

Release Agents:

Release agents as a rule have lipophilic properties and are added as arule to the spray suspensions. They prevent agglomeration of the coresduring film-coating. Preferably, talc, Mg or Ca stearate, ground silicicacid, kaolin or non-ionic emulsifiers having an HLB of between 3 and 8are employed. Customary use amounts for release agents in the coatingand binding agents according to the invention are between 0.5 to 100% byweight based on the copolymer (a).

In a particularly advantageous embodiment, the addition of the releaseagent takes place as a non-film-coating final layer. The applicationtakes place as a powder (in concentrated form, 90–100% strength) or fromaqueous suspension containing 5–30% solids content by spraying. Theamount necessary is lower than in the case of incorporation into thepolymer layer and is 0.1–2% based on the weight of the pharmaceuticalform.

Pigments:

The addition only rarely takes place in the form of the soluble dye. Asa rule, aluminium or iron oxide pigments are dispersed. Titanium dioxideserves as a white pigment. Customary use amounts for pigments in thecoating and binding agents according to the invention [lacuna] between20 and 60% by weight, based on the polymer mixture. Because of the highpigment binding power, however, amounts of up to 100% by weight can alsobe processed.

In a particularly advantageous embodiment, use of the pigment takesplace as a non-film-coating final layer. The application takes place asa powder (in concentrated form, 90–100% strength) or from aqueoussuspension containing 5–30% solids content by spraying. The amountnecessary is lower than in the case of incorporation into the polymerlayer and is 0.1–2% based on the weight of the pharmaceutical form.

In principle, of course, all substances employed must be toxicologicallyacceptable and be used in pharmaceuticals without risk for patients.

Further additives can also be plasticizers. Customary amounts arebetween 0 and 50, preferably 0 to 20, in particular 0 to 10, % byweight. Particularly preferably, however, at most 5% by weight of or noplasticizers are present, as the formulations are often already elasticenough due to the presence of the components (c) [sic] and additionalplasticizers can lead to undesired stickiness.

Depending on type (lipophilic or hydrophilic) and amount added,plasticizers can influence the functionality of the polymer layer.Plasticizers achieve a lowering of the glass transition temperature bymeans of physical interaction with the polymer and, depending on theamount added, promote film-coating. Suitable substances as a rule have amolecular weight of between 100 and 20,000 and contain one or morehydrophilic groups in the molecule, e.g. hydroxyl, ester or aminogroups.

Examples of suitable plasticizers are alkyl citrates, glycerol esters,alkyl phthalates, alkyl sebacates, sucrose esters, sorbitan esters,diethyl sebacate, dibutyl sebacate and polyethylene glycols 200 to12,000. Preferred plasticizers are triethyl citrate (TEC),acetyltriethyl citrate (ATEC) and dibutyl sebacate (DBS). Mention mayfurthermore be made of esters which as a rule are liquid at roomtemperature, such as citrates, phthalates, sebacates or castor oil.Esters of citric acid and sebacic acid are preferably used.

The addition of the plasticizer to the formulation can be performed in aknown manner, directly, in aqueous solution or after thermalpretreatment of the mixture. Mixtures of plasticizers can also beemployed.

The Production Process

The components (a), (b) and (c) are blended with one another at ambientor elevated temperature with or without addition of water and if desiredof a pharmaceutical active compound and the further customary additivesand the coating and binding agent is prepared by melting, casting,spreading, spraying or granulating. The film-coating of the coating andbinding agent here is a prerequisite for the functional effect inpharmaceutical forms.

The film-coating is carried out, independently of the applicationprocess, by supply of energy. This can take place via convection (heat),radiation (infrared or microwaves) or conduction. Water employed forapplication as a suspending agent evaporates here, and if desired avacuum can also be used in order to accelerate the evaporation. Thetemperature necessary for the film-coating depends on the combination ofthe components employed.

Use of the Formulation According to the Invention for the Production ofBinding Agents:

The use as binding agents is carried out, for example, by spraying theaqueous polymer suspension onto active-compound-free cores(nonpareilles) with simultaneous addition of powdered active compoundsor mixtures thereof. A further embodiment is the spraying on of theaqueous polymer suspension together with active compounds dissolved orsuspended therein.

Use of the Formulation According to the Invention for the Production ofCoating Agents:

Preformed carriers for the coatings are capsules, tablets, granules,pellets, crystals of regular or irregular shape. The size of granules,pellets or crystals is between 0.01 and 2.5 mm, that of tablets between2.5 and 30.0 mm. Capsules consist of gelatine, starch or cellulosederivatives.

As a rule, powders and crystals contain 100% of the biologically activesubstance. Preformed carriers contain from about 0.1 to 99% of thebiologically active substance or of the pharmaceutical active compoundand to [sic] 1 to 99.9% by weight of further pharmaceutical excipients.

Customary preparation processes are direct compression, compression ofdry, moist or sintered granules, extrusion and subsequent rounding,moist or dry granulation or direct pelletting (e.g. on plates) or bybinding of powders (powder layering) to active-compound-free spheres(nonpareilles) or active-compound-containing particles.

In addition to the active compound, they can contain furtherpharmaceutical excipients: binding agents, such as cellulose and itsderivatives, polyvinylpyrrolidone (PVP), moisturizing agents,disintegration promoters, lubricants, disintegrants, (meth)acrylates,starch and its derivatives, sugar solubilizers or others.

Of particular importance is the disintegration time of the cores, whichinfluences the release of the active compound. Today, shortdisintegration times of below 5, or below 10 min, are demanded in thedisintegration test according to Ph. Eur. Longer disintegration timesare therefore problematical, because additional coatings further delaythe release of the active compound and can call the therapeutic effectinto question. The threshold value today is regarded as a disintegrationtime of 30 min. Testing is carried out in water and artificial gastricjuice (0.1 N HCl). The cores employed are homogeneous or have a layeredstructure. If engravings are embedded in the surfaces, as far as theseshould be covered possible by coatings but only slightly filled in. Thelayer thickness employed according to the invention of the polymerpowder varies greatly and depends on the processing procedure or theamount of additives. It is between 1 and 100 μm, preferably between 10and 50 μm. On customary tablets, this corresponds to a polymerapplication of 0.5 to 5% by weight.

Coated microparticles can be compressed according to K. Lehmann et al.,Drugs made in Germany 37, 2, 53–60 (1994) and T. E. Beckert et al.,International Journal of Pharmaceutics 143, (1996), 13–23 to givedisintegrating tablets without significant influence on the function ofthe polymer.

The function of the film-coated polymer layer in the finalpharmaceutical form can be varied:

-   -   Protection against harmful environmental influences due to        moisture, gases, light etc.    -   Odour or taste isolation    -   Marking by means of colour    -   Mechanical stabilization    -   Isolation of incompatible ingredients    -   Avoidance of adhesion to the mucous membranes    -   Temporally delayed release of active compound    -   pH-controlled release of active compound    -   Isolation of cores from further coatings

The low viscosity of the polymer mixture in aqueous dispersion isadvantageous even at high solid contents of up to 30%, as engravings onthe surface of tablets are reproduced in detail.

Particularly advantageous is the good protective and isolating action ofthe polymer mixture according to the invention with simultaneously lowinfluence on the tablet disintegration. Even with low polymerapplications of 1% by weight, a taste isolation of more than 30 sec isalready achieved. Thicker coatings with a copolymer of methylmethacrylate, butyl methacrylate and dimethylaminoethyl methacrylate inthe ratio 25:25:50 (EUDRAGIT®EPO) improve the taste concealment, butwithout prolonging the disintegration time in 0.1 N HCl. Likewiseadvantageous is the permissible covering of coloured cores by coatingswith a high pigment content. One particular embodiment is the embeddingof a second active compound in the coating on anactive-compound-containing core.

Application to the Formulation According to the Invention for Productionon Carriers

The formulation according to the invention can be applied bygranulating, pouring, spreading or by means of spray application inpowder form, as a melt or in aqueous suspension. Water is here usedmainly as a vehicle in order to apply thin coatings uniformly onspherical cores, e.g. by spraying. For coatings, spreading processes aremoreover employed. The process employed depends mainly on the carrierchosen. Dry powders are applied by spreading or dusting, if appropriatealso using electrostatic forces. The film-coating can take place by theaction of heat. For implementation it is crucial here that uniform,closed layers are formed.

For application processes according to the prior art see, for example,Bauer, Lehmann, Osterwald, Rothgang, “Überzogene Arzneiformen” (CoatedPharmaceutical Forms”) Wissenschaftliche Verlagsgesellschaft mbHStuttgart, Chap. 7, pp. 165–196.

Properties relevant to application, tests required and specificationsare listed in pharmacopoeias.

Details can be taken from the customary textbooks, e.g.:

-   -   Voigt, R. (1984): Lehrbuch der pharmazeutischen Technologie        (Textbook of Pharmaceutical Technology); Verlag Chemie        Weinheim—Beerfield Beach/Florida—Basle.    -   Sucker, H., Fuchs, P., Speiser, P.: Pharma-zeutische Technologie        (Pharmaceutical Technology), Georg Thieme Verlag Stuttgart        (1991), in particular Chapter 15 and 16, pp. 626–642.    -   Gennaro, A. R. (Editor), Remington's Pharmaceutical Sciences,        Mack Publishing Co., Easton, Pa. (1985), Chapter 88, pp.        1567–1573.    -   List, P. H. (1982): Arzneiformenlehre (Pharmaceutical Form        Theory), Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart.        Biologically Active Substances:

The pharmaceutical substances employed for the purpose of the inventionare intended to be used on or in the human or animal body in order

-   1. to cure, to alleviate, to prevent or to detect diseases,    suffering, bodily injury or pathological symptoms.-   2. to be able to recognize the condition, the state or the function    of the body or mental states.-   3. to replace active compounds or bodily fluids produced by the    human or animal body.-   4. to defend against, to eliminate or to render harmless pathogens,    parasites or exogenous substances or-   5. to influence the condition, the state or the function of the body    or mental states.

Customary pharmaceuticals can be taken from reference works, such as theRote Liste or the Merck Index. The formulation according to theinvention is suitable for the administration of fundamentally anydesired pharmaceutical active compounds which can preferably beadministered in isolated or protected form, such as antidepressants,beta-receptor blockers, antidiabetics, analgesics, antiinflammatories,antirheumatics, antihypotensives, antihypertensives,psychopharmaceuticals, tranquillizers, antiemetics, muscle relaxants,glucocorticoids, agents for the treatment of ulcerative colitis orCrohn's disease, antiallergics, antibiotics, antiepileptics,anticoagulants, antimycotics, antitussives, arteriosclerotic agents,diuretics, enzymes, enzyme inhibitors, antigout agents, hormones andtheir inhibitors, cardiac glycosides, immunotherapeutics and cytokines,laxatives, hypolipidaemics, gastrointestinal therapeutics, antimigraineagents, mineral preparations, otologicals, antiparkinson agents, thyroidgland therapeutics, spasmolytics, platelet aggregation inhibitors,vitamins, cytostatics and metastasis inhibitors, phytopharmaceuticals,chemotherapeutics and amino acids. Examples of suitable active compoundsare acarbose, nonsteroidal antirheumatics, cardiac glycosides,acetylsalicylic acid, virustatics, aclarubicin [sic], acyclovir,cisplatin, actinomycin, alpha- and beta-sympathomimetics, (allopurinol[sic], alosetrone, alprostadil, prostaglandins, amantadine, ambroxole,amlodipine, methotrexate, S-aminosalicylic acid, amitriptyline,amlodipine [sic], amoxicillin, anastrozole, atenolol, atorvastatin,azathioprine, balsalazide, beclo-methasone, betahistine, bezafibrate,bicalutamide, diazepam and diazepam derivatives, budesonide, bufexamac,buprenorphine, methadone, calcium salts, potassium salts, magnesiumsalts, candesartan, carbamazepine, captopril, cefalosporins [sic],celetoxib, cetirizine, chenodeoxycholic acid, ursodeoxycholic acid,theophylline and theophylline derivatives, trypsins, cimetidine,clarithromycin, clavulanic acid, clindamycin, clobutinol, clonidine,cotrimazole, codeine, caffeine, vitamin D and derivatives of vitamin D,colestyramine, cromoglycic acid, coumarin and coumarin derivatives,cysteine, cytarabine, cyclophosphamide, cyclosporin, cyproterone,cytarabine [sic], dapiprazole, desogestrel, desonide, dihydralazine,diltiazem, ergot alkaloids, dimenhydrinate, dimethyl sulphoxide,dimeticone [sic], dipyridarnoi [sic], domperidone and domperidan [sic]derivatives, donepzil, dopamine, doxazosine, doxorubicin, doxylamine,dapiprazole [sic], benzodiazepines, diclofenac, glycoside antibiotics,desipramine, econazole, ACE inhibitors, enalapril, ephedrine,epinephrine. epoetin and epoetin derivatives, morphinans, calciumantagonists, irinotecan, modafinil, orlistate, peptide antibiotics,phenytoin, riluzole, risedronate, sildenafil, topiramate, macrolideantibiotics, esomeprazole, oestrogen and oestrogen derivatives, gestagenand gestagen derivatives, testosterone and testosterone derivatives,androgen and androgen derivatives, ethenzamide, etofenamate, etofibrate,fenofibrate, etophylline, etoposide, famciclovir, famotidine,felodipine, fenofibrate, fentanyl, fenticonazole, gyrase inhibitors,fluconazole, fludarabine, flunarizine, fluorouracil, fluoxetin,flubiprofen, ibuprofen, flutamide, fluvastatin, follitropin, formoterol,fosfomycin, furosemide, fusidic acid, galantamine, gallopamil,ganciclovir, gemfibrozil, gentamicin, ginkgo, St. John's wort,glibenclamide, urea derivatives as oral antidiabetics, glucagon,glucosamine and glucosamine derivatives, glutathione, glycerol andglycerol derivatives, hypothalamic hormones, goserelin, gyraseinhibitors [sic], guanethidine, halofantrin, haloperidol, heparin andheparin derivatives, hyaluronic acid, hydralazine, hydrochlorothiazideand hydrochlorothiazide derivatives, salicylates, hydroxyzine,idarubicin, ifosfamide, imipramine, indomethacin, indoramine, insulin,interferons, iodine and iodine derivatives, isoconazole,isoproprenaline, glucitol and glucitol derivatives, itraconazole,ketoconazole, ketoprofen, ketotifen, lacidipine, lansoprazole, levodopa,levomethadone, thyroid hormones, lipoic acid and lipoic acidderivatives, lisinopril, lisuride, lofepramine, lomustine, loperamide,loratadine, maprotilin, mebendazole, mebeverine, meclozine, mefenamicacid, mefloquin, meloxicam, mepindolol, meprobamate, meropenem,mesalazine, mesuximide, metamizole, metformin, methotrexate,methylphenidate, methylprednisolone, metixen, metoclopramide,metoprolol, metronidazole, mianserin, miconazole, minocycline,minoxidil, misoprostol, mitomycin, mizolastine, moexipril, morphine andmorphine derivatives, evening primrose, nalbuphine, naloxone, tilidine,naproxen, narcotine, natamycin, neostigmine, nicergoline, nicethamide,nifedipine, niflumic acid, nimodipine, nimorazole, nimustine,nisoldipine, adrenaline and adrenaline derivatives, norfloxacin,novamine sulphone, noscapine, nystatin, ofloxacin, olanzapine,olsalazine, omeprazole, omoconazole, odansetrone, orlistat, oseltamivir,oxaceprol, oxacillin, oxiconazole, oxymetazoline, pantoprazole,paracetamol, paroxetin, penciclovir, oral penicillins, pentazocine,pentifylline, pentoxifylline, perphenazine, pethidine, plant extracts,phenazone, pheniramine, barbituric acid derivatives, phenylbutazone,phenytoin, pimozide, pindolol, piperazine, piracetam, pirenzepine,piribedil, piroxicam, pramipexol, pravastatin, prazosine, procaine,promazine, propiverine, propranolol, propyphenazone, prostaglandins,protionamide, proxyphylline, quetiapine, quinapril, quinaprilate,ramipril, ranitidine, reproterol, reserpine, ribavirin, rifampicin,risperidone, ritonavir, ropinirol, rosiglitazone, roxatidine,roxithromycin, ruscogenin, rutoside and rutoside derivatives, sabadilla,salbutamol, salmeterol, scopolamine, selegenin, sertaconazole,sertindole, sertralione [sic], silicates, simvastatin, sitosterin,sotalol, spaglumic acid, sparfloxacin, spectinomycin, spiramycin,spirapril, spironolactone, stavudine, streptomycin, sucralfate,sufentanil, sulbactam, sulphonamides, sulfasalazine, sulpiride,sultamicillin, sultiam, sumatriptan, suxamethonium chloride, tacrin,tacrolimus, taliolol, tamoxifen, taurolidine, tazorotene, tegaserod,temazepam, teniposide, tenoxicam, terazosine, terbinafine, terbutaline,terfenadine, terlipressin, tertatolol, tetracyclines, tetryzoline,theobromine, theophylline, butizine, thiamizole, phenothiazines,thiotepa, tiagabine, tiapride, propionic acid derivatives, ticlopidine,timolol, tinidazole, tioconazole, tioguanine, tioxolone, tiropramide[sic], tizanidine, tolazoline, tolbutamide, tolcapone, tolnaftate,tolperisone, topotecan, torasemide, anti6strogens [sic], tramadol,tramazoline, trandolapril, tranylcypromine, trapidil, trazodone,triamcinolone and triamcinolone derivatives, triamterene, trifluperidol,trifluridine, trimethoprim, trimipramine, tripelennamine, triprolidine,trifosfamide, tromantadine, trometamol, tropalpine, troxerutine,tulobuterol, tyramine, tyrothricin, urapidil, ursodeoxycholic acid[sic], chenodeoxycholic acid [sic], valaciclovir, valdecoxib, valproicacid, vancomycin, vecuronium chloride, venlafaxin, verapamil, vidarabin,vigabatrin, viloxazine, vinblastine, vincamine, vincristine, vindesine,vinorelbin, vinpocetin, viquidil, warfarin, xantinol nicotinate,xipamide, zafirlukast, zalcitabin, zanamivir, zidovudine, zolmitriptan,zolpidem, zoplicone, zotepine and the like.

If desired, the active compounds can also be used in the form of theirpharmaceutically acceptable salts or derivatives, and in the case ofchiral active compounds both optically active isomers and racemates ordiastereoisomer mixtures can be employed. If desired, the compositionsaccording to the invention can also contain two or more pharmaceuticalactive compounds.

Examples of particularly preferred active compounds are acetylsalicylicacid, cabenoxolone, cefalotin, epinefrine [sic], imipramine, potassiumiodide, ketoprofen, levodopa, nitrazepam, nitroprusside, oxytetracyclineHCl, promethazine, omeprazole or other benzimidazole derivatives andstreptomycin.

Administration Forms:

In principle, the pharmaceutical forms described can be used directly byoral administration. The granules, pellets or particles preparedaccording to the invention can be dispensed in gelatine capsules,sachets or in suitable multi-dose containers having a dosage device.Administration is carried out in solid form or suspended in liquids. Bymeans of compression, if applicable after admixture of furtherexcipients, tablets are obtained from which disintegrate afteradministration and which release usually coated subunits. Likewiseconceivable is the embedding of agglomerates in polyethylene glycol orlipids for the production of suppositories or vaginal pharmaceuticals.Coated tablets are packed in blister packs or multi-dose containers andremoved by the patient directly before administration.

Active compound classes and substances which can often produced a bittertaste and can be formulated advantageously using the coating and bindingagents according to the invention are, for example:

-   Analgesics and antirheumatics:    -   paracetamol, diclofenac, aceclofenac, ibuprofen, ketoprofen,        flurbiprofen, levacetylmethadol, oxycodone-   Psychopharmaceuticals:    -   prometazine, donepizil, modafinil, nefazodone, reboxetin,        sertindole, sertralin-   Antibiotics:    -   erythromycin, roxithromycin, clarithromycin, grepafloxacin,        ciprofloxacin, levofloxacin, sparfloxacin, trovafloxacin,        nevirapin-   Beta-blockers    -   propranolol, metoprolol, bisoprolol, nebivolol-   Antidiabetics:    -   metformin, miglitol, repaglinide-   H1 antihistaminics    -   diphenhydramine, fexofenadine, mizolastine-   H2 antihistaminics    -   cimetidine, nizatidine, ticlopidine, cetridine, ranitidine-   Vitamins: thiamine nitrate; Others: quinidine sulphate, amiloprilose    HCl, pseudoephedrine HCl, sildenafil, topiramate, granisetrone,    rebamipide, quinine HCl

EXAMPLES Examples 1 to 14

Dispersion or dissolution of a copolymer of methyl methacrylate, butylmethacrylate and dimethylaminoethyl methacrylate in the ratio 25:25:50with an average particle size of 15 μm (EUDRAGIT® E PO).

Preparation Procedure:

Completely demineralized water is preadded to a vessel then thecomponents (a), (b) and (c) according to claim 1 added with stirring bymeans of a bladed stirrer stirred at about 400 revolutions/min [sic].The entire preparation is monitored [lacuna] 400 times magnificationusing a polarization microscope.

The dispersion or solution has a dry matter content of 15%, and is oflow viscosity.

Example 15: a copolymer of methyl methacrylate, butyl methacrylate, anddimethylamino ethyl methacrylate in the ratio 25:25:50 (EUDRAGIT® E100)dissolved in isopropanol/acetone (6:4) is used. Copolymer content 12.5%by weight.

The experiments listed below in Table 1 are calculated on a batch sizeof 100 g, the additions being relative to the amount of copolymer.

Abbreviations:

rel. to=relative to

RT=room temperature

TABLE 1 Preparation of the coating and binding agent Component (b)Component (c) Example [% rel. to [% rel. to Dispersing DispersingDispersion Properties of WVP No. copolymer] copolymer] temperature time[h] complete the dried films [g/m²/d] 1. 7 15 RT about 3 yes flexible,clear 324 Na lauryl lauric acid sulphate 2. 7 15 RT about 4 yesflexible, 324 Na lauryl myristic acid slightly sulphate clouded 3. 7 15RT about 6 yes flexible, 168 Na lauryl palmitic acid slightly sulphateclouded 4. 7 15 RT about 6 yes flexible, 179 Na lauryl stearic acidslightly sulphate clouded 5. 7 20 RT about 6 yes flexible, 213 Na laurylstearic acid slightly sulphate clouded 6. 7 30 RT about 5 yes flexible,289 Na lauryl stearic acid slightly sulphate clouded 7. 7 30 RT to about4 yes flexible, 186 Na lauryl stearic acid 73° C. slightly sulphateclouded 8. 10 10 RT about 6 yes flexible, 125 Na lauryl stearic acidslightly sulphate clouded 9. 10 15 RT about 6 yes brittle, 96 Na laurylstearic acid slightly sulphate clouded 10.  10 15 RT about 24 yesflexible, clear 264 Na lauryl lauryl alcohol sulphate 11.  10 10 RTabout 3 yes flexible, clear 112 Na lauryl lauryl alcohol sulphateNegative Examples

Component (b) Component (c) Example [% rel. to [% rel. to DispersingDispersing Dispersion Properties of WVP No. copolymer] copolymer]temperature time [h] complete the dried films [g/m[hu 2/d] 12. 7 15 RTabout 2 yes brittle 454 Na lauryl sebacinic crystals sulphate acid 13. 715 RT — no — — Na lauryl behenic acid sulphate Prior art 14. 7 15 444 Nalauryl diethyl sulphate sebacate 15. — — EUDRAGIT ® E 12.5 from organicsolution 336 (isopropanol-acetone = 6:4)Water Vapour Permeabilities, Film Properties

Films of the dispersions prepared are drawn on condenser paper by meansof a 250 μm doctor blade and allowed to dry overnight at RT. The driedfilms having a layer thickness of 30–35 μm (condenser paper additionallyincluded) are then investigated for water vapour permeability accordingto DIN 53122 at 23° C., 85% relative humidity. For each dispersion, 6tests are carried out in parallel.

Description of the Test:

3 g of silica gel, granulation 1–3 mm/Merck, having a moistureindicator, are weighed into a plane-ground test cell made of glass(internal diameter 2 cm) and dried at 110° C. for 3 hours. The groundsurface of the test cell is greased with silicone paste so that afterapplication of the film an airtight closure is guaranteed. The selectedfilms [lacuna] applied and covered with a likewise plane-groundsilicone-greased glass ring. By means of this film surface of 3.14 cm²which is now formed, the water vapour permeability (WVP) at 23° C. and85% rel. humidity is determined gravimetrically over a period of time of16 and 24 hours.WVD(g/m ² /d)=24/t×Δm/A×24

-   t=experimental time in hours between the weighings from which the    weight difference Δm is determined, i.e. 18−2=16 or 24−2=22-   Δm=amount of water diffused through the film in g after 16 hours and    22 hours; the weight of the test cell+film obtained after 2 hours    counts as a reference value.-   A=test area of the film in cm²=3.14 cm²

The average value is calculated from the results (16 and 22 h) of atleast 5 test cells.

Coatings from the Dispersions of the above Examples

The spray experiments were carried out in an Erweka coating pan with 2.5to 3 kg batch size placebo tablets, partly replaced by quinidinesulphate tablets or silica gel tablets. The polymer application is 2 to4 mg/cm².

The release agent is manly homogenized in the dispersion by means of anUltra Turrax for about 15 min and then sprayed onto the rotating tabletsusing a two-channel spray pistol Walter NBA nozzle 1.2 mm, spraypressure of 0.8 to 1 bar. The material temperature can be between 27 to[sic] 34° C., while the spray velocity can be 2.2 to 3 g/min/kg. Dryingis then carried out in a 40° C. recirculating drying oven for 4 h.

TABLE 2 Experiment Release agent according to (% rel. to Disintegrationtime (min) Run No. recipe no. Copo) mg of Copo/cm² MS H₂O Tasteisolation 16. 4. 42 pigment 2 2.1 5.3 >8 min 17. 4. 50 talc 2 1.3 3.6 n.d. 4 1.7 7.3 n. d. 18. 14.  35 Mg stearate 2 1.7 17.2 n. d. 4 2 21.5 n.d. 19. 8. 15 Mg stearate 2 1.2 2.2 >6 min 15 pigments 20. 15.  50 talc 21.1 >60 n. d. 4 1.7 >60 n. d. 21. 4. 35 Mg stearate 2 1.7 3.9 n. d. 41.97 6.4 n. d. Copo = copolymer The disintegration time was determinedfollowing according to [sic] the method of the European pharmacopoeia.

TABLE 3 Water absorption of silica gel tablets in an air-conditionedcabinet at 40° C. and 75% rel. humidity with 4 mg of copolymer/cm².Water absorption [%] after after after after Recipe after 1 h after 2 h4 h 6 h 10 h 24 h According to 0.48 1.07 2.16 3.04 4.80 9.06 Example 20According to 0.67 1.62 2.71 3.79 5.93 11.19 Example 18 According to 0.340.69 1.36 1.92 3.11 6.55 Example 21 Comparison value: 2.68 5.31 9.4612.30 14.80 15.10 HPMC Comparison value: 7.71 11.94 14.61 15.10 15.1615.64 silica gel tablets (without coating) The water absorption wasdetermined gravimetrically.

1. A process for producing a coating and binding agent comprising: (a)50 to 90% by weight, of a copolymer comprising free-radical-polymerizedC1 to C4 esters of acrylic or methacrylic acid and (meth)acrylatemonomers which contain functional tertiary amino groups, wherein thecopolymer is present in powder form having an average particle size of1–40 μm, (b) 3 to 15% by weight, based on (a), of an emulsifier havingan HLB of at least 14, and (c) 5 to 50% by weight, based on (a), of aC₁₂- to C₁₈-monocarboxylic acid or a CH₃(CH₂)_(n)OH compound where n isfrom 11 to 17, said process comprising, blending or mixing (a), (b) and(c) with or without addition of water, a pharmaceutical active compound,one or more additives or mixtures thereof, and forming the coating andbinding agent by melting, casting, spreading, spraying or granulating,wherein the coating and binding agent has a water vapor permeability ofat most 300 (g/m²/d) as measured according to DIN 53
 122. 2. The processaccording to claim 1, further comprising applying a release agent to thecoating and binding agent.
 3. The process according to claim 1, furthercomprising applying a pigment to the coating and binding agent.
 4. Acoating and binding agent prepared by the process according to claim 1.5. A pharmaceutical form comprising the coating and binding agentaccording to claim 4 and a pharmaceutical active compound.
 6. Thepharmaceutical form according to claim 5, comprising amoisture-sensitive pharmaceutical active compound selected from thegroup consisting of analgesics, antirheumatics, active compounds for thetreatment of gastric ulcers, antibiotics, antihypotensives,antidepressants, thyroid gland therapeutics, antiparkinson activecompounds, anxiolytics and neuroleptics.
 7. The pharmaceutical formaccording to claim 6, wherein the moisture-sensitive pharmaceuticalactive compound is selected from the group consisting of acetylsalicylicacid, carbenoxolone, cefalotin, epinefrine, imipramine, potassiumiodide, ketoprofen, levodopa, nitrazepam, nitroprusside, oxytetracyclineHCl, promethazine, omeprazole, benzimidazole derivatives andstreptomycin.
 8. A method comprising coating a pharmaceuticalcomposition with the coating and binding agent of claim
 4. 9. Amoisture-isolating coating comprising the coating and binding agentaccording to claim
 4. 10. A taste-isolating coating comprising thecoating and binding agent of claim
 4. 11. The coating and binding agentof claim 4, comprising a C₁₂- to C₁₈-monocarboxylic acid; wherein theC₁₂- to C₁₈-monocarboxylic acid is lauric acid.
 12. The coating andbinding agent of claim 4, comprising a C₁₂- to C₁₈-monocarboxylic acid;wherein the C₁₂- to C₁₈-monocarboxylic acid is myristic acid.
 13. Thecoating and binding agent of claim 4, comprising a C₁₂- toC₁₈-monocarboxylic acid; wherein the C₁₂- to C₁₈-monocarboxylic acid ispalmitic acid.
 14. The coating and binding agent of claim 4, comprisinga C₁₂- to C₁₈-monocarboxylic acid; wherein the C₁₂- toC₁₈-monocarboxylic acid is stearic acid.
 15. The coating and bindingagent of claim 4, comprising a CH₃(CH₂)_(n)OH compound; wherein theCH₃(CH₂)_(n)OH compound is lauryl alcohol.
 16. The coating and bindingagent of claim 4, comprising a CH₃(CH₂)_(n)OH compound; wherein theCH₃(CH₂)_(n)OH compound is stearyl alcohol.
 17. The process of claim 1,wherein the coating and binding agent has a water vapor permeability ofat most 200 (g/m²/d) as measured according to DIN 53
 122. 18. Thecoating and binding agent of claim 4, which has a water vaporpermeability of at most 200 (g/m²/d) as measured according to DIN
 53122. 19. The process of claim 1, wherein (a), (b), (c) are blended withthe addition of the pharmaceutical active compound.
 20. The process ofclaim 1, wherein (a), (b), (c) are blended without the addition of thepharmaceutical active compound.